Exploring and anticipating supramolecular synthons: from fundamental science to practical applications

Doctor of PhilosophyDepartment of ChemistryChrister B. AakeröyFour different methods; molecular electrostatic potentials (MEPs), hydrogen-bond energies (HBE), hydrogen-bond propensities (HBP) and hydrogen-bond coordination (HBC) were used for mapping out the structural landscape of twelve pyrazole and twelve thiazole based molecules. In seven out of eight crystal structures obtained in pyrazoles, a combination of HBE and HBP predicted the experimentally observed synthons correctly. In all eight crystal structures obtained in thiazoles, the synthons were predicted correctly using all four methods. A series of co-crystallizations between twelve pyrazole with twenty carboxylic acids (240 experiments), and twelve thiazole with twenty carboxylic acids (240 experiments) were carried out to build an experimental library that could be used for evaluating the ability of electrostatics, energies, propensities and molecular complementarity methods to rationalize the observed intermolecular interactions. The results suggested that a combination of electrostatics and molecular complementarity are essential for identifying the predominant molecular recognition events in the pyrazole based study, and methods such as MEPs, HBE, and HBP all predicted the observed synthons in co-crystals of the thiazole-based molecules. In order to examine competition between hydrogen and halogen bonds, and to synthesize ternary co-crystals, four thiazole based molecules were co-crystallized with 15 hydrogen-bond donors and one halogen bond donor resulting in new co-crystals in 44 out of 60 experiments, and the crystal structures of two ternary co-crystals were obtained. A series of eight unactivated and activated amide functionalized molecules were synthesized to establish a supramolecular halogen-bond hierarchy. The positive electrostatic potential on the halogen atoms was enhanced through an sp-hybridized carbon and electron-withdrawing fluoro group(s) next to amide group. Tetraflourinated and iodoethynyl based molecules were identified as the most effective halogen-bond donors and were therefore least successful for co-crystal synthesis. In order to predict crystallizability of 83 drug-like molecules a molecule, logistic regression approach was employed using molecular descriptors such as molecular weight, rotatable bond, surface area, heteroatom, melting temperature, glass transition temperature, and molecular shape/volume. Four different models were developed, and the success rate was above 85% (using experimental DSC data for the crystallization classification). Finally, the solid-form landscape of urea was explored using full interaction maps (FIMs), and data from the CSD to develop optimum protocols for synthesizing co-crystals of this compound. As a result, 49 of 60 attempted reactions produced new co-crystals. Moreover, the goal of reducing solubility and lowering hygroscopicity of the parent compound was achieved, which, in turn, offers new opportunities for a slow-release fertilizer with limited hygroscopicity thereby reducing many current problems of transport, handling, and storage of urea

Patients' understanding of anticoagulant therapy in a multiethnic population

To investigate whether knowledge and perceptions of antithrombotic therapy differ between ethnic groups in the UK, we conducted a cross-sectional questionnaire survey of patients attending anticoagulation clinics in three Birmingham teaching hospitals. 180 consecutive patients were recruited—135 white European, 29 Indo-Asian, 16 Afro-Caribbean. The average knowledge score was 5.5 out of 9, with no significant differences between the groups. Indo-Asians were significantly less likely than the other groups to know the name of the anticoagulant they were taking (warfarin) and Afro-Caribbeans to know the condition for which they were being anticoagulated. Few patients of any group were able to specify more than one side-effect of warfarin or the dose they were on. In logistic regression analysis the factors associated with a low score were age >61 years, having been born outside the UK, and the perception of difficulty in comprehension. Nearly half the Indo-Asians felt unable to understand what was said to them in the clinic, and 62% expressed a preference for a doctor of the same ethnic group. Although there were no significant between-group differences, this study points to gaps in the knowledge of patients from ethnic minorities and to deficiencies in the provision of information. In patient education, these groups should receive special attention

A critical appraisal of current management practices for infant regurgitation - Recommendations of a working party

Regurgitation is a common manifestation in infants below the age of 1 year and a frequent reason of counselling of general practitioners and paediatricians. Current management starts with postural and dietary measures, followed by antacids and prokinetics. Recent issues such as an increased risk of sudden infant death in the prone sleeping position and persistent occult gastro-oesophageal reflux in a subset of infants receiving milk thickeners or thickened 'anti-regurgitation formula' challenge the established approach. Therefore, the clinical practices for management of infant regurgitation have been critically evaluated with respect to their efficacy, safety and practical implications. The updated recommendations reached by the working party on the management of infant regurgigation contain five phases: (1A) parental reassurance; (1B) milk-thickening agents; (2) prokinetics; (3) positional therapy as an adjuvant therapy; (4A) H2-blockers; (4B) proton pump inhibitors; (5) surgery.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Current concepts and issues in the management of regurgitation of infants: A reappraisal: Management guidelines from a working party

Regurgitation in infants is a common problem. Recent issues, such as the increased risk of sudden infant death in the prone sleeping position, the finding of persisting occult gastro-oesophageal reflux with feed thickeners, and the increasing awareness of the cost-benefit ratio of medications may challenge the currently recommended management approach. A round table was organized to elaborate on the impact of (i) the pro supine sleeping campaigns in relation to sudden infant death and (ii) advancement in medical treatment on therapeutic strategies in regurgitating infants. The participants were opinion leaders from Europe and North America (Belgium, Canada, France, UK, Italy, Switzerland and The Netherlands). The importance of parental reassurance is stressed. As a consequence of the supine sleeping campaigns aiming to decrease the incidence of sudden infant death syndrome, the "prone elevated sleeping position" is no longer advised as a first-line therapeutic approach, although it is still recommended in "complicated reflux". It is emphasized that milk thickeners are an adequate therapeutic tool for regurgitation, but not in reflux disease. According to the literature, the efficacy of (alginate-)antacids, although very popular in some countries, is questionable. These recommendations will be of interest to first-line paediatricians, since about 40% of their patients, according to the literature, present because of regurgitation.SCOPUS: re.jFLWNAinfo:eu-repo/semantics/publishe